1. Field of the Invention
This invention relates to a bioadhesive tablet containing at least one bioadhesive adjuvant and at least one lubricant, with at least one surface of said tablet comprising concentric or parallel, straight and/or curved depressions, and to a method for producing said bioadhesive tablets as well as to pharmaceuticals in the form of said bioadhesive tablets.
2. Prior Art
Bioadhesive pharmaceuticals that temporarily adhere to biological tissue while they release their active agent have been known for about 10 years. These bioadhesive or mucosa-adhesive pharmaceuticals are expected to solve bioavailability problems resulting from a too short retention time of the active agents at the place of resorption by adhering to mucosae. In particular, bioadhesive pharmaceuticals can bring about preferred resorption of the active agent at specified mucosae, e.g. of the gastro-intestinal tract.
Adhesion of this type of pharmaceuticals to the place of resorption is facilitated by bioadhesive polymers among which hydrogel-forming substances such as cellulose derivatives (hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (NaCMC)), cross-linked polyacrylic acid (Carbopol.RTM.) and other carboxyvinyl polymers (Eudragit.RTM.), tragacanth gum and alginates are said to have the greatest efficacy. A survey (Duchene, D.; Touchard, F; Peppas, N. A.: Drug Dev. Ind. Pharm. 14, 283 (1988) ) described bioadhesive pharmaceuticals, e.g. tablets, films, plaster, gels and capsules that act locally or on the system and are primarily administered orally (buccally) but can also be applied perorally (gastro-intestinal tract), periocularly, nasally, vaginally, or rectally. Carboxyvinyl polymers (Carbopol.RTM. or Polycarbophil.RTM.) and cellulose derivatives (hydroxypropyl cellulose (HPC), HEC or NaCMC) or mixtures of both component were mentioned as bioadhesive polymers for these pharmaceuticals. In particular, carboxyvinyl polymers and compounds derived from them are suited as bioadhesive polymers (Peppas, N. A.; Buri, P. A.; J. Controlled Release 2, p. 257 (1985); Park, K.; Cooper, S. L.; Robinson, J. R.: Hydrogels Med. Pharm. 3, p. 151 (1987)).
DD 285 551 A5 relates to a method for the production of bioadhesive pharmaceuticals, for example, tablets, granulates or mucilages containing a copolymerisate that is capable of swelling in water and comprises a maximum of 25 percent by mass of monomers with carboxyl functions, mainly characterized by a content of foreign matter of up to 0.56 percent by mass, and further characterized in that it is produced using a maximum of 0.5 percent by mass of an anionic emulgator and a maximum of 0.06 percent by mass of an initiator.
The solid bioadhesive pharmaceuticals known so far are decomposed slowly, as a rule. Frequently the unchanged form of the pharmaceutical, for example, microparticles but most frequently two- or multilayer tablets, is brought into contact with the tissue. Only a more or less narrowly limited area is therefore available for resorbing the active agent. This area can be further reduced by the beginning swelling of the respective form of application depending on the bioadhesive polymer used. This is the case, for example, for a coated bioadhesive tablet that is capable of swelling and consists of a core containing the active agent and a bioadhesive coating (Ishida, M.; Machida, Y.; Nambu, N.; Nagai, T.: Chem. Pharm. Bull. 29, p. 810 (1981)).
Bioadhesive microspheres presented recently also contain the active agent in their core and are coated with a layer of a bioadhesive polymer (Junginger, H. E.; Lehr, C. M.: Dtsch. Apoth. Ztg. 130, p. 791 (1990)). A diffusion layer can be formed during the swelling process that adversely affects the passage of the pharmaceutical.
Thus bioadhesive tablets such as buccal tablets are mostly described as two- or multilayer tablets that release the active agent in a controlled way (Junginger, H. E.; de Vries, M. E.; Bodde, H. E.: Dtsch. Apoth. Ztg. 131, p. 1337 (1991)). These tablets adhere to the tissue at first due to capillary effects, and later, following hydration and swelling, due to bonds resulting from the interdiffusing bioadhesive polymer.
Other bioadhesive tablets, especially buccal tablets (Veillard, M. in: Gurny, R.; Junginger, H. E. (eds.) "Bioadhesion--Possibilities and Future Trends", p. 124, APV-Paperback, Wiss. Verlagsgesellschaft, Stuttgart 1990), only show limited swelling and are therefore particularly suited for long-term adhesion to the tissue. As an exception, bioadhesive mucilages, i.e. aqueous preparations (Robinson, J. R.: S.T.P. Pharma 5, p. 839 (1989)) or a tablet that swells to form a mucilage (DE 4 139 883 A1) are used. These show lower adhesion to the tissue than the solid forms or their decomposition products (Saettone, M. F.; Chetoni, P.; Torracca, M. T.; Burgalassi, S.; Giannaccini, B.: Int. J. Pharm. 51, p. 203 (1989)), and they have the known disadvantages of being susceptible to microorganisms and containing unstable active agents.
Furthermore, a number of fast decaying pharmaceuticals can be found that do not come close to the pharmaceuticals of the invention because of their rapid decomposition. For example, U.S. Pat. No. 5,007,790 relates to tablets and capsules containing polymers capable of swelling for application in the gastro-intestinal tract.
U.S. Pat. No. 4,886,669 describes tablets comprising microparticles that contain the active agent, a decomposition adjuvant, and a swelling agent. The product of rapid decomposition of the tablets in water is a high-viscosity suspension. It is known, however, that there is no direct connection between viscosity and bioadhesion (Dittgen, M.; Oestereich, S.; Dittrich, F.: Pharmazie 44, p. 460 (1989), Satoh, K.; Takayama, K.; Machida, Y.; Suzuki, Y.; Nakagaki, M.; Nagai, T.: Chem. Pharm. Bull. 37, p. 1366 (1989)).
It is the problem of the present invention to overcome the disadvantages of the bioadhesive tablets known so far. In particular, it is a problem of the invention to improve the passage of the active agents contained therein through the mucosa.